Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors

Idiopathic pulmonary fibrosis (IPF)
is an interstitial lung disease
characterized by a progressive-fibrosing phenotype. IPF has been associated
with aberrant HDAC activities confirmed by our immunohistochemistry
studies on HDAC6 overexpression in IPF lung tissues. We herein developed
a series of novel hHDAC6 inhibitors, having low inhibitory
potency over hHDAC1 and hHDAC8,
as potential pharmacological tools for IPF treatment. Their inhibitory
potency was combined with low in vitro and in vivo toxicity. Structural analysis of 6h and structure–activity relationship studies contributed to
the optimization of the binding mode of the new molecules. The best-performing
analogues were tested for their efficacy in inhibiting fibrotic sphere
formation and cell viability, proving their capability in reverting
the IPF phenotype. The efficacy of analogue 6h was also
determined in a validated human lung model of TGF-β1-dependent
fibrogenesis. The results highlighted in this manuscript may pave
the way for the identification of first-in-class molecules for the
treatment of IPF.